Chemical compounds

ABSTRACT

The present invention provides compounds of formula (I) including stereoisomers, prodrugs and pharmaceutically acceptable salts or solvates thereof, wherein R is aryl or heteroaryl, each of which may be substituted by 1 to 4 groups selected from: halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, —C(O)R 5 , nitro, —NR 6 R 7 , cyano, and a group R 8 ; R 1  is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, halogen, NR 6 R 7  or cyano; R 2  is hydrogen, C3-C7 cycloalkyl, or a group R 9 ; R 3  is C3-C7 cycloalkyl, or a group R 9 ; or R 2  and R 3  together with N form a 5-14 membered heterocycle, which may be substituted 1 to 3 R 10  groups; R 4  is hydrogen, C1-C6 alkyl, halogen or halo C1-C6 alkyl; R 5  is a C1-C4 alkyl, —OR 6  or NR 6 R 7 ; R 6  is hydrogen or C1-C6 alkyl; R 7  is hydrogen or C1-C6 alkyl; R 8  is a 5-6 membered heterocycle, which may be saturated or may contain one to three double bonds, and which may be substituted by 1 or more R 11  groups; R 9  is a C1-C6 alkyl that may be substituted by one or more groups selected from: C3-C7 cycloalkyl, C1-C6 alkoxy, halo C1-C6 alkoxy, hydroxy, halo C1-C6 alkyl; R 10  is a group R 8 , C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, hydroxy, halogen, nitro, cyano, C(O)NR 6 R 7 , phenyl which may be substituted by 1 to 4 R 11  groups; R 11  is C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, hydroxy, halogen, nitro, cyano, or C(O)NR 6 R 7 ; X is carbon or nitrogen; n is 1 or 2; to processes for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of conditions mediated by corticotropin-releasing factor (CRF).

[0001] The present invention relates to bicyclic derivatives, toprocesses for their preparation, to pharmaceutical compositionscontaining them and to their use in therapy.

[0002] The first corticotropin-releasing factor (CRF) was isolated fromovine hypothalami and identified as a 41-amino acid peptide (Vale etal., Science 213: 1394-1397,1981). CRF has been found to produceprofound alterations in endocrine, nervous and immune system function.CRF is believed to be the major physiological regulator of the basal andstress-release of adrenocorticotropic hormone (“ACTH”), Bendorphin andother proopiomelanocortin (“POMC”)-derived peptides from the anteriorpituitary (Vale et al., Science 213: 1394-1397,1981).

[0003] In addition to its role in stimulating the production of ACTH andPOMC, CRF appears to be one of the pivotal central nervous systemneurotransmitters and plays a crucial role in integrating the body'soverall response to stress.

[0004] Administration of CRF directly to the brain elicits behavioral,physiological and endocrine responses identical to those observed for ananimal exposed to a stressful environment.

[0005] Accordingly, clinical data suggests that CRF receptor antagonistsmay represent novel antidepressant and/or anxiolytic drugs that may beuseful in the treatment of the neuropsychiatric disorders manifestinghypersecretion of CRF.

[0006] The first CRF receptor antagonists were peptides (see, e.g.,Rivier et al., U.S. Pat. No. 4,605,642; Rivier et al., Science 224:889,1984). While these peptides established that CRF receptorantagonists can attenuate the pharmacological responses to CRF, peptideCRF receptor antagonists suffer from the usual drawbacks of peptidetherapeutics including lack of stability and limited oral activity. Morerecently, small molecule CRF receptor antagonists have been reported.

[0007] WO 95/10506 describes inter alia compounds of general formula (A)with general CRF antagonist activity

[0008] wherein Y may be CR29; V may be nitrogen, Z may be carbon, R3 maycorrespond to an amine derivative and R4 may be taken together with R29to form a 5-membered ring and is —CH(R28) when R29 is —CH(R30). Thereare no specific disclosures of compounds corresponding to thisdefinition.

[0009] WO 95/33750 also describes compounds of general formula (B)having CRF antagonistic activity,

[0010] in which A and Y may be nitrogen and carbon and B may correspondto an amine derivative. There are no specific disclosures of compoundscorresponding to this definition.

[0011] WO 98/08846 describes compounds of general formula (C) having CRFantagonistic activity,

[0012] wherein A may be carbon, G may be nitrogen or carbon, B may be anamino derivative and the other groups have the meanings as defined.

[0013] Due to the physiological significance of CRF, the development ofbiologically-active small molecules having significant CRF receptorbinding activity and which are capable of antagonizing the CRF receptorremains a desirable goal. Such CRF receptor antagonists would be usefulin the treatment of endocrine, psychiatric and neurologic conditions orillnesses, including stress-related disorders in general.

[0014] While significant strides have been made toward achieving CRFregulation through administration of CRF receptor antagonists, thereremains a need in the art for effective small molecule CRF receptorantagonists. There is also a need for pharmaceutical compositionscontaining such CRF receptor antagonists, as well as methods relating tothe use thereof to treat, for example, stress-related disorders. Thepresent invention fulfills these needs, and provides other relatedadvantages.

[0015] In particular the invention relates to novel compounds which arepotent and specific antagonists of corticotropin-releasing factor (CRF)receptors.

[0016] The present invention provides compounds of formula (I) includingstereoisomers, prodrugs and pharmaceutically acceptable salts orsolvates thereof

[0017] wherein

[0018] R is aryl or heteroaryl, each of which may be substituted by 1 to4 groups selected from:

[0019] halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, —C(O)R₅, nitro, —NR₆R₇,cyano, and a group R₈;

[0020] R₁ is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, haloC1-C6 alkyl, halo C1-C6 alkoxy, halogen, NR₆R₇ or cyano;

[0021] R₂ is hydrogen, C3-C7 cycloalkyl, or a group R₉;

[0022] R₃ is C3-C7 cycloalkyl, or a group R₉; or

[0023] R₂ and R₃ together with N form a 5-14 membered heterocycle, whichmay be substituted by 1 to 3 R₁₀ groups;

[0024] R₄ is hydrogen, C1-C6 alkyl, halogen or halo C1-C6 alkyl;

[0025] R₅ is a C1-C4 alkyl, —OR₆ or —NR₆R₇;

[0026] R₆ is hydrogen or C1-C6 alkyl;

[0027] R₇ is hydrogen or C1-C6 alkyl;

[0028] R₈ is a 5-6 membered heterocycle, which may be saturated or maycontain one to three double bonds, and which may be substituted by 1 ormore R₁₁ groups;

[0029] R₉ is a C1-C6 alkyl that may be substituted by one or more groupsselected from: C3-C7 cycloalkyl, C1-C6 alkoxy, haloC1-C6 alkoxy,hydroxy, haloC1-C6 alkyl;

[0030] R₁₀ is a group R₉, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy,halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy,hydroxy, halogen, nitro, cyano, C(O)NR₆R₇, phenyl which may besubstituted by 1 to 4 R₁₁ groups;

[0031] R₁₁ is C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, hydroxy,halogen, nitro, cyano, or C(O)NR₆R₇;

[0032] X is carbon or nitrogen;

[0033] n is 1 or 2.

[0034] Acid addition salts of the free base amino compounds of thepresent invention may be prepared by methods well known in the art, andmay be formed from organic and inorganic acids. Suitable organic acidsinclude maleic, malic, fumaric, benzoic, ascorbic, succinic,methanesulfonic, p-toluensulfonic, acetic, oxalic, propionic, tartaric,salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic,stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids.Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric,phosphoric, and nitric acids. Thus, the term “pharmaceuticallyacceptable salt” of structure (I) is intended to encompass any and allacceptable salt forms.

[0035] The solvates may, for example, be hydrates.

[0036] References hereinafter to a compound according to the inventioninclude both compounds of formula (I) and their pharmaceuticallyacceptable acid addition salts together with pharmaceutically acceptablesolvates.

[0037] In addition, prodrugs are also included within the context ofthis invention. Prodrugs are any covalently bonded carriers that releasea compound of structure (I) in vivo when such prodrug is administered toa patient. Prodrugs are generally prepared by modifying functionalgroups in a way such that the modification is cleaved, either by routinemanipulation or in vivo, yielding the parent compound. Prodrugs include,for example, compounds of this invention wherein hydroxy, amine orsulfhydryl groups are bonded to any group that, when administered to apatient, cleaves to form the hydroxy, amine or sulfhydryl groups. Thus,representative examples of prodrugs include (but are not limited to)acetate, formate and benzoate derivatives of alcohol, sulfhydryl andamine functional groups of the compounds of structure (1). Further, inthe case of a carboxylic acid (—COOH), esters may be employed, such asmethyl esters, ethyl esters, and the like.

[0038] With regard to stereoisomers, the compounds of structure (I) mayhave chiral centers and may occur as recemates, racemic mixtures and asindividual enantiomers or diastereomers. All such isomeric forms areincluded within the present invention, including mixtures thereof.Furthermore, some of the crystalline forms of the compounds of structure(I) may exist as polymorphs, which are included in the presentinvention.

[0039] The term C1-C6 alkyl as used herein as a group or a part of thegroup refers to a linear or branched alkyl group containing from 1 to 6carbon atoms; examples of such groups include methyl, ethyl, propyl,isopropyl, n-butyl, isobutyl, tert butyl, pentyl or hexyl.

[0040] The term C3-C7 cycloalkyl group means a non aromatic monocyclichydrocarbon ring of 3 to 7 carbon atom such as, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; whileunsaturated cycloalkyls include cyclopentenyl and cyclohexenyl, and thelike.

[0041] The term halogen refers to a fluorine, chlorine, bromine oriodine atom.

[0042] The term halo C1-C6 alkyl, or halo C1-C2 alkyl means an alkylgroup having one or more carbon atoms and wherein at least one hydrogenatom is replaced with halogen such as for example a trifluoromethylgroup and the like.

[0043] The term C2-C6 alkenyl defines straight or branched chainhydrocarbon radicals containing one or more double bond and having from2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl,3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl or3-hexenyl and the like.

[0044] The term C1-C6 alkoxy group may be a linear or a branched chainalkoxy group, for example methoxy, ethoxy, propoxy, prop-2-oxy, butoxy,but-2-oxy or methylprop-2-oxy and the like.

[0045] The term halo C1-C6 alkoxy group may be a C1-C6 alkoxy group asdefined before substituted with at least one halogen, preferablyfluorine, such as OCHF₂, or OCF₃.

[0046] The term C2-C6 alkynyl defines straight or branched chainhydrocarbon radicals containing one or more triple bond and having from2 to 6 carbon atoms including acetylenyl, propynyl, 1-butynyl,1-pentynyl, 3-methyl-1-butynyl and the like.

[0047] The term aryl means an aromatic carbocyclic moiety such asphenyl, biphenyl or naphthyl.

[0048] The term heteroaryl means an aromatic heterocycle ring of 5 to 10members and having at least one heteroatom selected from nitrogen,oxygen and sulfur, and containing at least 1 carbon atom, including bothmono-and bicyclic ring systems.

[0049] Representative heteroaryls include (but are not limited to)furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl,isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl,isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl,thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, triazolyl, tetrazolyl,and quinazolinyl.

[0050] The term 5-14 membered heterocycle means a 5 to 7-memberedmonocyclic, or 7-to 14-membered polycyclic, heterocycle ring which iseither saturated, unsaturated or aromatic, and which contains from 1 to4 heteroatoms independently selected from nitrogen, oxygen and sulfur,and wherein the nitrogen and sulfur heteroatoms may be optionallyoxidized, and the nitrogen heteroatom may be optionally quaternized,including bicyclic rings in which any of the above heterocycles arefused to a benzene ring as well as tricyclic (and higher) heterocyclicrings. The heterocycle may be attached via any heteroatom or carbonatom. Heterocycles include heteroaryls as defined above. Thus, inaddition to the aromatic heteroaryls listed above, heterocycles alsoinclude (but are not limited to) morpholinyl, pyrrolidinonyl,pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl,oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, andthe like.

[0051] The term 5-6 membered heterocycle means, according to the abovedefinition, a 5-6 monocyclic heterocyclic ring which is eithersaturated, unsaturated or aromatic, and which contains from 1 to 4heteroatoms independently selected from nitrogen, oxygen and sulfur, andwherein the nitrogen and sulfur heteroatoms may be optionally oxidized,and the nitrogen heteroatom may be optionally quaternized. Heterocyclesinclude heteroaryls as defined above. The heterocycle may be attachedvia any heteroatom or carbon atom. Thus, the term include (but are notlimited to) morpholinyl, pyridinyl, pyrazinyl, pyrazolyl, thiazolyl,triazolyl, imidazolyl, oxadiazolyl, oxazolyl, pyrrolidinonyl,pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl,oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl,tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, andthe like.

[0052] Representative compounds of this invention include the followingstructure (Ia) and (Ib)

[0053] In one preferred embodiment in which n is 1, according to thedefinition of the compounds of formula (I) above, the CRF receptorantagonists of this invention have structure (Ia), and, when n is 2,then the CRF receptor antagonists of this invention have structure (Ib),wherein R, R₁, R₂ and R₃ are defined as above.

[0054] Further representative compounds of this invention includecompounds of general formula (I) in which

[0055] R₂ and R₃ together with N form a 5-14 membered heterocyclicgroup, which may be substituted by 1 to 3 R₁₀ groups; such R₁₀ groupsare defined as above.

[0056] Depending upon the choice of X, the CRF receptor antagonists ofthis invention include compounds of formula (IIa) and (IIb), in whichthe group NR₂R₃ represents a 5-6 membered heterocyclic group, which maybe substituted by 1 to 3 R₈ groups.

[0057] In particular compounds of formula (IIIa) and (IIIb) are included

[0058] in which R₁, R and R₈ have the meanings as defined before.

[0059] Examples of such compounds are reported in the Experimental Part.

[0060] Even more preferred embodiments of the invention include, but arenot limited to, compounds of the formula (I), (Ia), (Ib), (IIa), (IIb),(IIIa), (IIIb):

[0061] wherein:

[0062] R₁ is C1-C3 alkyl group or halo C1-C3 alkyl group, preferablymethyl or trifluoromethyl;

[0063] R₄ is hydrogen; and

[0064] R is an aryl group selected from: 2,4-dichlorophenyl,2-chloro-4-methylphenyl, 2-chloro-4-trifluoromethyl,2-chloro-4-methoxyphenyl, 2,4,5-trimethylphenyl, 2,4-dimethylphenyl,2-methyl-4-methoxyphenyl, 2-methyl-4-chlorophenyl,2-methyl-4-trifluoromethyl, 2,4-dimethoxyphenyl,2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4-chlorophenyl,3-methoxy-4-chlorophenyl, 2,5-dimethoxy-4-chlorophenyl,2-methoxy-4-isopropylphenyl, 2-methoxy-4-trifluoromethylphenyl,2-methoxy-4-isopropylphenyl, 2-methoxy-4-methylphenyl,2-trifluoromethyl-4-chlorophenyl, 2,4-trifluoromethylphenyl,2-trifluoromethyl-4-methylphenyl, 2-trifluoromethyl-4-methoxyphenyl,2-bromo-4-isopropylphenyl, 2-methyl-4-cyanophenyl,2-chloro-4-cyanophenyl, 4-methyl-6-dimethylaminopyridin-3-yl,3,5-dichloro-pyridin-2-yl, 2,6-bismethoxy-pyridin-3-yl and3-chloro-5-trichloromethyl-pyridin-2-yl.

[0065] Preferred compounds according to the invention are:

[0066]1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine;

[0067]1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine;

[0068]3-methyl-4-[6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl]-benzonitrile;

[0069]4-[6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl]-3-trifluoromethyl-benzonitrile;

[0070]6-methyl-1-(2-methyl-4-trifluoromethoxy-phenyl)-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine;

[0071]1-(2,4-bis-trifluoromethyl-phenyl)-7-methyl-5-(3-thiazol-2-yl-pyrazol-1-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine;

[0072]1-(4-methoxy-2-methyl-phenyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

[0073]1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-4-(3-morpholin-4-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

[0074]1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-4-(3-pyridin-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

[0075] 4-[1,3′]bipyrazolyl-1′-yl-1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine.

[0076] In general, the compounds of structure (I) may be made accordingto the organic synthesis techniques known to those skilled in thisfield, as well as by the representative methods set forth in theExamples.

[0077] Compounds of formula (I), and salts and solvates thereof, may beprepared by the general methods outlined hereinafter. In the followingdescription, the groups R, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁,and n have the meanings as previously defined for compounds of formula(I) unless otherwise stated.

[0078] Compounds of formula (IIa) may be conveniently prepared accordingto the following Scheme 1:

[0079] in which

[0080] step a stands for conversion of the leaving group L, selected ina group consisting from: halogen or reactive residue of sulphonic acid(e.g. mesylate, tosylate), preferably chloride, in the amino group ofcompounds (III), by reaction with the suitable amine NR₂R₃ in basicconditions;

[0081] step b stands for reduction of the ester group with a suitablereducing agent (such as DIBAl—H) to hydroxy group of compounds (IV);

[0082] step c stands for oxidation of the hydroxy group with a suitableoxidising agent (such as Dess-Martin periodinane) to aldehyde group ofcompound (V);

[0083] step d stands for formation of the aldehyde group of compounds(VII) by Wittig reaction in the usual conditions, through formation ofenol ether followed by acid hydrolysis (step e);

[0084] step f stands for reduction of the aldehyde group with a suitablereducing agent (such as NaBH₄) to hydroxy group of compounds (VIII);

[0085] step g stands for conversion of the hydroxy group in the suitableprotecting group of compounds (IX)(such as TBS:tert-butyldimethylsilyl);

[0086] step h stands for Buchwald reaction by coupling with the suitableamine RNH₂;

[0087] step i stands for deprotection reaction to give the hydroxy groupof compounds (XI);

[0088] step l stands for intramolecular cyclisation by heating afterconversion of the hydroxy group of compounds (XI) in a suitable leavinggroup (such as bromide, by reaction with CBr₄ and PPh₃) to give thefinal compounds (IIa).

[0089] Alternatively, compounds of formula (IIa) may be convenientlyprepared according to the following Scheme 2:

[0090] in which

[0091] step a′ stands for conversion of the hydroxy group in a suitableleaving group L′ of compounds (XII), which, independently from L, hasthe same definition (e.g mesylate, by reaction with MsCl in Et₃N);

[0092] step b′ stands for conversion of L′ in the cyano derivative ofcompounds (XIII) by reaction with, e.g. KCN in an aprotic dipolarsolvent, like DMF;

[0093] step c′ stands for reduction of the cyano group with a suitablereducing agent agent (such as BH₃-THF) to the amino group of compound(XIV);

[0094] step d′ stands for intramolecular cyclisation of compounds (XIV)by heating in a suitable solvent (such as NMP) at high temperature;

[0095] step e′ stands for reduction of the aldehyde group with asuitable reducing agent (such as NaBH₄) to hydroxy group of compounds(VIII);

[0096] step f′ corresponds to previous step h.

[0097] Compounds of formula (IIb) may be conveniently prepared accordingto the following Scheme 3:

[0098] in which:

[0099] step a″ corresponds to previous step d;

[0100] step b″ corresponds to previous step e;

[0101] step c″ corresponds to previous step f;

[0102] step d″ corresponds to previous step g;

[0103] step e″ corresponds to previous step h;

[0104] step f″ corresponds to previous step i;

[0105] step g″ corresponds to previous step l;

[0106] Compounds of formula (II) are known compounds or may be preparedaccording to known methods in the literature.

[0107] Compounds of formula (IIIa) and (IIIb) may be prepared accordingto the previous Schemes 1, 2 and 3, once prepared the heterocyclicreactive residue according to known methods to the skilled in the art.

[0108] Examples of suitable hydroxy protecting group includetrihydrocarbyl silyl ethers such as the trimethylsilyl ort-butyldimethylsilyl ether. The hydroxyl protecting groups may beremoved by well-known standard procedures (such as those described inProtective Groups in Organic Chemistry, pages 46-119, Edited by J F WMcOmie (Plenum Press, 1973)). For example when Pg is at-butyldimethylsilyl group, this may be removed by treatment withtriethylamine trihydrofluoride.

[0109] Pharmaceutical acceptable salts may also be prepared from othersalts, including other pharmaceutically acceptable salts, of thecompound of formula (I) using conventional methods.

[0110] The compounds of formula (I) may readily be isolated inassociation with solvent molecules by crystallisation or evaporation ofan appropriate solvent to give the corresponding solvates.

[0111] When a specific enantiomer of a compound of general formula (I)is required, this may be obtained for example by resolution of acorresponding enantiomeric mixture of a compound of formula (I) usingconventional methods. Thus the required enantiomer may be obtained fromthe racemic compound of formula (I) by use of chiral HPLC procedure.

[0112] The subject invention also includes isotopically-labeledcompounds, which are identical to those recited in formulas I andfollowing, but for the fact that one or more atoms are replaced by anatom having an atomic mass or mass number different from the atomic massor mass number usually found in nature. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, andchlorine, such as ³H, ¹¹C, ¹⁴C, ¹⁸F, ¹²³I and ¹²⁵I.

[0113] Compounds of the present invention and pharmaceuticallyacceptable salts of said compounds that contain the aforementionedisotopes and/or other isotopes of other atoms are within the scope ofthe present invention. Isotopically-labeled compounds of the presentinvention, for example those into which radioactive isotopes such as ³H,¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. ¹¹C and ⁸F isotopes are particularly useful in PET(positron emission tomography), and ¹²⁵I isotopes are particularlyuseful in SPECT (single photon emission computerized tomography), alluseful in brain imaging. Further, substitution with heavier isotopessuch as deuterium, i.e., ²H, can afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements and, hence, may bepreferred in some circumstances. Isotopically labeled compounds offormula I and following of this invention can generally be prepared bycarrying out the procedures disclosed in the Schemes and/or in theExamples below, by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

[0114] The CRF receptor antagonists of the present invention demonstrateactivity at the CRF receptor site including CRF 1 and CRF 2 receptorsand may be used in the treatment of conditions mediated by CRF or CRFreceptors.

[0115] The effectiveness of a compound as a CRF receptor antagonist maybe determined by various assay methods. Suitable CRF antagonists of thisinvention are capable of inhibiting the specific binding of CRF to itsreceptor and antagonizing activities associated with CRF. A compound ofstructure (I) may be assessed for activity as a CRF antagonist by one ormore generally accepted assays for this purpose, including (but notlimited to) the assays disclosed by DeSouza et al. (J. Neuroscience 7:88,1987) and Battaglia et al. (Synapse 1: 572,1987).

[0116] The CRF receptors-binding assay was performed by using thehomogeneous technique of scintillation proximity (SPA). The ligand bindsto recombinant membrane preparation expressing the CRF receptors whichin turn bind to wheatgerm agglutinin coated SPA beads. In theExperimental Part will be disclosed the details of the experiments.

[0117] With reference to CRF receptor binding affinities, CRF receptorantagonists of this invention have a Ki less than 10 μm.

[0118] Compounds of the invention are useful in the treatment of centralnervous system disorders where CRF receptors are involved. In particularin the treatment or prevention of major depressive disorders includingbipolar depression, unipolar depression, single or recurrent majordepressive episodes with or without psychotic features, catatonicfeatures, melancholic features, atypical features or postpartum onset,the treatment of anxiety and the treatment of panic disorders. Othermood disorders encompassed within the term major depressive disordersinclude dysthymic disorder with early or late onset and with or withoutatypical features, neurotic depression, post traumatic stress disordersand social phobia; dementia of the Alzheimer's type, with early or lateonset, with depressed mood; vascular dementia with depressed mood; mooddisorders induced by alcohol, amphetamines, cocaine, hallucinogens,inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics andother substances; schizoaffective disorder of the depressed type; andadjustment disorder with depressed mood. Major depressive disorders mayalso result from a general medical condition including, but not limitedto, myocardial infarction, diabetes, miscarriage or abortion, etc.

[0119] Compounds of the invention are also useful in the treatment orprevention of schizophrenic disorders including paranoid schizophrenia,disorganised schizophrenia, catatonic schizophrenia, undifferentiatedschizophrenia, residual schizoprenia.

[0120] Compounds of the invention are useful as analgesics. Inparticular they are useful in the treatment of traumatic pain such aspostoperative pain; traumatic avulsion pain such as brachial plexus;chronic pain such as arthritic pain such as occurring in osteo-,rheumatoid or psoriatic arthritis; neuropathic pain such aspost-herpetic neuralgia, trigeminal neuralgia, segmental or intercostalneuralgia, fibromyalgia, causalgia, peripheral neuropathy, diabeticneuropathy, chemotherapy-induced neuropathy, AIDS related neuropathy,occipital neuralgia, geniculate neuralgia, glossopharyngeal neuralgia,reflex sympathetic dystrophy, phantom limb pain; various forms ofheadache such as migraine, acute or chronic tension headache,temporomandibular pain, maxillary sinus pain, cluster headache;odontalgia; cancer pain; pain of visceral origin; gastrointestinal pain;nerve entrapment pain; sport's injury pain; dysmennorrhoea; menstrualpain; meningitis; arachnoiditis; musculoskeletal pain; low back paine.g. spinal stenosis; prolapsed disc; sciatica; angina; ankylosingspondyolitis; gout; burns; scar pain; itch; and thalamic pain such aspost stroke thalamic pain.

[0121] Compounds of the invention are also useful for the treatment ofdysfunction of appetite and food intake and in circumstances such asanorexia, anorexia nervosa and bulimia.

[0122] Compounds of the invention are also useful in the treatment ofsleep disorders including dysomnia, insomnia, sleep apnea, narcolepsy,and circadian ritmic disorders.

[0123] Compounds of the invention are also useful in the treatment orprevention of cognitive disorders. Cognitive disorders include dementia,amnestic disorders and cognitive disorders not otherwise specified.

[0124] Furthermore compounds of the invention are also useful as memoryand/or cognition enhancers in healthy humans with no cognitive and/ormemory deficit.

[0125] Compounds of the invention are also useful in the treatment oftolerance to and dependence on a number of substances. For example, theyare useful in the treatment of dependence on nicotine, alcohol,caffeine, phencyclidine (phencyclidine like compounds), or in thetreatment of tolerance to and dependence on opiates (e.g. cannabis,heroin, morphine) or benzodiazepines; in the treatment of cocaine,sedative ipnotic, amphetamine or amphetamine-related drugs (e.g.dextroamphetamine, methylamphetamine) addiction or a combinationthereof.

[0126] Compounds of the invention are also useful as anti-inflammatoryagents. In particular they are useful in the treatment of inflammationin asthma, influenza, chronic bronchitis and rheumatoid arthritis; inthe treatment of inflammatory diseases of the gastrointestinal tractsuch as Crohn's disease, ulcerative colitis, inflammatory bowel disease(IBD) and non-steroidal anti-inflammatory drug induced damage;inflammatory diseases of the skin such as herpes and eczema;inflammatory diseases of the bladder such as cystitis and urgeincontinence; and eye and dental inflammation.

[0127] Compounds of the invention are also useful in the treatment ofallergic disorders, in particular allergic disorders of the skin such asurticaria, and allergic disorders of the airways such as rhinitis.

[0128] Compounds of the invention are also useful in the treatment ofemesis, i.e. nausea, retching and vomiting. Emesis includes acuteemesis, delayed emesis and anticipatory emesis. The compounds of theinvention are useful in the treatment of emesis however induced. Forexample, emesis may be induced by drugs such as cancer chemotherapeuticagents such as alkylating agents, e.g. cyclophosphamide, carmustine,lomustine and chlorambucil; cytotoxic antibiotics, e.g. dactinomycin,doxorubicin, mitomycin-C and bleomycin; anti-metabolites, e.g.cytarabine, methotrexate and 5-fluorouracil; vinca alkaloids, e.g.etoposide, vinblastine and vincristine; and others such as cisplatin,dacarbazine, procarbazine and hydroxyurea; and combinations thereof;radiation sickness; radiation therapy, e.g. irradiation of the thorax orabdomen, such as in the treatment of cancer; poisons; toxins such astoxins caused by metabolic disorders or by infection, e.g. gastritis, orreleased during bacterial or viral gastrointestinal infection;pregnancy; vestibular disorders, such as motion sickness, vertigo,dizziness and Meniere's disease; post-operative sickness;gastrointestinal obstruction; reduced gastrointestinal motility;visceral pain, e.g. myocardial infarction or peritonitis; migraine;increased intercranial pressure; decreased intercranial pressure (e.g.altitude sickness); opioid analgesics, such as morphine; andgastro-oesophageal reflux disease, acid indigestion, over-indulgence offood or drink, acid stomach, sour stomach, waterbrash/regurgitation,heartburn, such as episodic heartburn, nocturnal heartburn, andmeal-induced heartburn and dyspepsia.

[0129] Compounds of the invention are of particular use in the treatmentof gastrointestinal disorders such as irritable bowel syndrome (IBS);skin disorders such as psoriasis, pruritis and sunburn; vasospasticdiseases such as angina, vascular headache and Reynaud's disease;cerebral ischeamia such as cerebral vasospasm following subarachnoidhaemorrhage; fibrosing and collagen diseases such as scleroderma andeosinophilic fascioliasis; disorders related to immune enhancement orsuppression such as systemic lupus erythematosus and rheumatic diseasessuch as fibrositis; and cough.

[0130] Compounds of the invention are useful for the treatment ofneurotoxic injury which follows cerebral stroke, thromboembolic stroke,hemorrhagic stroke, cerebral ischemia, cerebral vasospam, hypoglycemia,hypoxia, anoxia, perinatal asphyxia cardiac arrest.

[0131] The invention therefore provides a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof for use in therapy,in particular in human medicine.

[0132] There is also provided as a further aspect of the invention theuse of a compound of formula (I) or a pharmaceutically acceptable saltor solvate thereof in the preparation of a medicament for use in thetreatment of conditions mediated by CRF.

[0133] In an alternative or further aspect there is provided a methodfor the treatment of a mammal, including man, in particular in thetreatment of condition mediated by CRF, comprising administration of aneffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt or a solvate thereof.

[0134] It will be appreciated that reference to treatment is intended toinclude prophylaxis as well as the alleviation of established symptoms.

[0135] Compounds of formula (I) may be administered as the raw chemicalbut the active ingredient is preferably presented as a pharmaceuticalformulation.

[0136] Accordingly, the invention also provides a pharmaceuticalcomposition which comprises at least one compound of formula (I) or apharmaceutically acceptable salt thereof and formulated foradministration by any convenient route. Such compositions are preferablyin a form adapted for use in medicine, in particular human medicine, andcan conveniently be formulated in a conventional manner using one ormore pharmaceutically acceptable carriers or excipients.

[0137] Thus compounds of formula (I) may be formulated for oral, buccal,parenteral, topical (including ophthalmic and nasal), depot or rectaladministration or in a form suitable for administration by inhalation orinsufflation (either through the mouth or nose).

[0138] For oral administration, the pharmaceutical compositions may takethe form of, for example, tablets or capsules prepared by conventionalmeans with pharmaceutically acceptable excipients such as binding agents(e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talcor silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbicacid). The preparations may also contain buffer salts, flavouring,colouring and sweetening agents as appropriate.

[0139] Preparations for oral administration may be suitably formulatedto give controlled release of the active compound.

[0140] For buccal administration the composition may take the form oftablets or formulated in conventional manner.

[0141] The compounds of the invention may be formulated for parenteraladministration by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form e.g. in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

[0142] The compounds of the invention may be formulated for topicaladministration in the form of ointments, creams, gels, lotions,pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointmentsand creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and/or gelling agents.Ointments for administration to the eye may be manufactured in a sterilemanner using sterilised components.

[0143] Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilisingagents, dispersing agents, suspending agents, thickening agents, orcolouring agents. Drops may be formulated with an aqueous or non-aqueousbase also comprising one or more dispersing agents, stabilising agents,solubilising agents or suspending agents. They may also contain apreservative.

[0144] The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

[0145] The compounds of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

[0146] For intranasal administration, the compounds of the invention maybe formulated as solutions for administration via a suitable metered orunitary dose device or alternatively as a powder mix with a suitablecarrier for administration using a suitable delivery device.

[0147] A proposed dose of the compounds of the invention is 1 to about1000 mg per day. It will be appreciated that it may be necessary to makeroutine variations to the dosage, depending on the age and condition ofthe patient and the precise dosage will be ultimately at the discretionof the attendant physician or veterinarian. The dosage will also dependon the route of administration and the particular compound selected.

[0148] Thus for parenteral administration a daily dose will typically bein the range of 1 to about 100 mg, preferably 1 to 80 mg per day. Fororal administration a daily dose will typically be within the range 1 to300 mg e.g. 1 to 100 mg.

EXAMPLES

[0149] In the Intermediates and Examples unless otherwise stated:

[0150] Melting points (m.p.) were determined on a Gallenkamp m.p.apparatus and are uncorrected. All temperatures refers to ° C. Infraredspectra were measured on a FT-IR instrument. Proton Magnetic Resonance(¹H-NMR) spectra were recorded at 400 MHz, chemical shifts are reportedin ppm downfield (d) from Me₄Si, used as internal standard, and areassigned as singlets (s), doublets (d), doublets of doublets (dd),triplets (t), quartets (q) or multiplets (m). Column chromathography wascarried out over silica gel (Merck AG Darmstaadt, Germany). Thefollowing abbreviations are used in text: EtOAc=ethyl acetate,cHex=cyclohexane, CH₂Cl₂=dichloromethane, Et₂O=dietyl ether,DMF=N,N′-dimethylformamide, DIPEA=N,N-diisopropylethylamine,DME=ethylene glycol dimethyl ether, MeOH=methanol, Et₃N=triethylamine,TFA=trifluoroacetic acid, THF=tetrahydrofuran,DIBAL-H=diisobutylaluminium hydride, DMAP=dimethylaminopyridine,LHMDS=lithiumhexamethyldisilazane; Tlc refers to thin layerchromatography on silica plates, and dried refers to a solution driedover anhydrous sodium sulphate; r.t. (RT) refers to room temperature.

Intermediate 1 2,4-Dichloro-6-methyl-nicotinic acid ethyl ester

[0151] The title compound was prepared according to an already publishedprocedure: Mittelbach, Martin; Synthesis, 1988, 6, p.479-80.

Intermediate 22-Chloro-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-nicotinic acid ethylester

[0152] To a solution of 2-(1H-pyrazol-3-yl)-1,3-thiazole (7.71 g, 1.05eq) in anh. DMF (61 mL), at 0° C., under N₂, was added NaH 60% inmineral oil (2.03 g, 1.05 eq) and the reaction mixture was stirred for10 min. at 0° C. and then for 1 hr at room temperature. Intermediate 1(11.34 g, 48.0 mmol) was then added as a solution in anh. DMF (35 mL) at0° C. and the resulting solution was heated at 110° C. for 3 hr. Thereaction was then quenched with water, extracted with EtOAc, washed withbrine, dried over anh. Na₂SO₄, filtered and concentrated in vacuo. Thecrude product was purified by flash chromatography (silica gel,cHex/EtOAc 7:3) to give 7.02 g of the title compound as a white solid.

[0153] NMR (¹H, CDCl₃): δ 7.91 (d, 1H), 7.91 (d, 1H), 7.41 (d, 1H), 7.31(s, 1H), 7.18 (d, 1H), 4.50 (q, 2H), 2.78 (s, 3H), 1.25 (t, 3H). MS(m/z): 349 [MH]⁺.

Intermediate 3[2-Chloro-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-3-yl]-methanol

[0154] To a solution of intermediate 2 (1.5 g, 4.3 mmol) in anh. CH₂Cl₂(30 mL), at −78° C., under N₂, was added DIBAl—H 1.0 M in cyclohexane(12.9 mL, 3.0 eq). The reaction mixture was stirred for 1 hr at −78° C.and then for 1 hr at room temperature. The reaction was then quenchedwith a saturated solution of Rochelle's salt, extracted with EtOAc,washed with brine, dried over anh. Na₂SO₄, filtered and concentrated invacuo. The crude product was purified by flash chromatography (silicagel, cHex/EtOAc 1:1) to give 1.02 g of the title compound as a whitesolid.

[0155] NMR (¹H, CDCl₃): δ 8.05 (d, 1H), 7.90 (d, 1H), 7.40 (d, 1H), 7.25(s, 1H), 7.10 (d, 1H), 4.65 (S, 2H), 4.0 (bs, 1H), 2.60 (s, 3H). MS(m/z): 307 [M]⁺.

Intermediate 42-Chloro-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridine-3-carbaldehyde

[0156] To a solution of intermediate 3 (150 mg, 0.5 mmol) in anh. CH₂Cl₂(5 mL), at room temperature, under N₂, was added the Dess Martinperiodinane (237 mg, 1.12 eq) and the reaction mixture was stirred for 1hr at room temperature. The reaction was then quenched with a solutionof 0.5 g of sodium thiosulfate dissolved in a saturated solution ofsodium bicarbonate, extracted with EtOAc, washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by flash chromatography (silica gel, cHex/EtOAc 1:1) to give124 mg of the title compound as a white solid.

[0157] NMR (¹H, CDCl₃): δ 10.4 (s, 1H), 8.0-7.9 (2d, 2H), 7.40 (2d, 2H),7.10 (s, 1H), 2.70 (s, 3H). MS (m/z): 305 [MH]⁺.

Intermediate 52-Chloro-3-(2-methoxy-vinyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridine

[0158] To a solution of (methoxymethyl)-triphenylphosphonium chloride(4.24 g, 3 eq) in anh. THF (20 mL), at 0° C., under N₂, was added n-BuLi1.6 M in cyclohexane (7.73 ml, 12.37 mmol) and the reaction mixture wasbrought to room temperature and then stirred for 15 min. A solution ofintermediate 4 (1.25 g, 4.1 mmol) in anh. THF (15 mL) was then added andthe reaction was stirred at room temperature for 1.5 hr. The reactionwas then quenched with water, extracted with EtOAc, washed with brine,dried over anh. Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified by flash chromatography (silica gel, cHex/EtOAc4:1) to give 961 mg of the title compound as a white solid (E:Z=3:2mixture, used as such in the next step).

[0159] NMR (¹H, CDCl₃) principal E product: δ 7.90 (m, 1H), 7.83 (m,1H), 7.38 (m, 1H), 7.05 (m, 1H), 7.00 (m, 1H), 6.51 (d, 1H), 5.63 (d,1H), 3.64 (s, 3H), 2.60 (s, 3H). MS (m/z): 333 [MH]⁺.

Intermediate 6[2-Chloro-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-3-yl]-acetaldehyde

[0160] To a solution of intermediate 5 (936 mg, 2.8 mmol) in anh. THF(15 mL) was added 6N HCl (21 ml, 45 eq) and the reaction mixture wasstirred at room temperature for 15 hr. The reaction was then quenchedwith sat. aq. NaHCO₃ until pH=7, extracted with EtOAc, washed withbrine, dried over anh. Na₂SO₄, filtered and concentrated in vacuo togive 893 mg of the title compound as a white solid, which was used inthe next step without further purification.

[0161] NMR (¹H, CDCl₃): δ 9.80 (s, 1H), 7.90-7.80 (2d, 2H), 7.70 (d,1H), 7.20 (d, 1H), 7.0 (s, 1H), 4.25 (s, 2H), 2.70 (s, 3H). MS (m/z):319 [MH]⁺.

Intermediate 72-[2-Chloro-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-3-yl]-ethanol

[0162] To a solution of intermediate 6 (903 mg, 2.84 mmol) in anh. MeOH(10 mL) were added CeCl₃ (700 mg, 1 eq) and NaBH₄ (107 mg, 1 eq) and thereaction mixture was stirred at room temperature for 5 min. The reactionwas then quenched with water, extracted with ethyl acetate, washed withbrine, dried over anh. Na₂SO₄, filtered and concentrated in vacuo togive 848 mg of the title compound as a white solid, which was used inthe next step without further purification.

[0163] NMR (¹H, CDCl₃): δ 8.00 (m, 2H), 7.50 (d, 1H), 7.20 (m, 2H), 4.25(t, 2H), 3.20 (t, 2H), 2.70 (s, 3H). MS (m/z): 321 [MH]⁺.

Intermediate 83-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-2-chloro-6-methyl-4-(3-thiazol-2yl-pyrazol-1-yl)-pyridine

[0164] To a solution of intermediate 7 (840 mg, 2.6 mmol) in anh. CH₂Cl₂(10 mL) were added 2,6-lutidine (0.67 ml, 2.2 eq) andtert-butyldimethylsilyl triflate (0.89 ml, 1.5 eq) and the reactionmixture was stirred at room temperature for 15 hr. The reaction was thenquenched with an aqueous solution of saturated NH₄Cl, extracted withEtOAc, washed with brine, dried over anh. Na₂SO₄, filtered andconcentrated in vacuo. The product was purified by flash chromatography(silica gel, cHex/EtOAc 3:2) to give 950 mg of the title compound as acolorless oil.

[0165] NMR (¹H, CDCl₃): δ 8.20 (d, 1H), 7.75 (d, 1H), 7.35 (d, 1H), 7.00(m, 2H), 4.00 (t, 2H), 3.05 (t, 2H), 2.55 (s, 3H), 0.80 (s, 9H), −0.10(s, 6H). MS (m/z): 435 [MH]⁺.

Intermediate 9(2,4-Bis-trifluoromethyl-phenyl)-[3-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-2-yl]-amine

[0166] To a solution of intermediate 8 (240 mg, 0.553 mmol) in anh. DME(1 mL) were added Pd₂(dba)₃ (51 mg, 0.1 eq),2-(dicyclohexylphosphino)-2′-methylbiphenyl (60 mg, 0.3 eq), K₃PO₄ (317mg, 3 eq) and 2,4-bis(trifluoromethyl) aniline (0.17 ml, 2 eq) and thereaction mixture was submitted to microwave irradiation (150 W, 100° C.,60 psi) for 20 min. The reaction was then quenched with an aqueoussolution of saturated NH₄Cl, extracted with EtOAc, washed with brine,dried over anh. Na₂SO₄, filtered and concentrated in vacuo. The productwas purified by flash chromatography (silica gel, cHex/EtOAc 9:1) togive 180 mg of the title compound as a colorless oil.

[0167] NMR (¹H, CDCl₃): δ 8.55 (d, 1H), 8.20 (bs, 1H), 7.90 (d, 1H),7.80 (m, 2H), 7.65 (dd, 1H), 7.40 (d, 1H), 7.05 (d, 1H), 6.85 (s, 1H),4.20 (t, 2H), 2.90 (t, 2H), 2.60 (s, 3H), 0.80 (s, 9H), 0.10 (s, 6H). MS(m/z): 628 [MH]⁺.

Intermediate 102-[2-(2,4-Bis-trifluoromethyl-phenylamino)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)pyridin-3-yl]-ethanol

[0168] To a solution of intermediate 9 (240 mg, 0.38 mmol) in anh. THF(5 mL) was added Et₃N.3HF (0.187 ml, 3 eq) and the reaction mixture wasstirred for 15 hr at room temperature. The reaction was then quenchedwith an aqueous solution of saturated NH₄Cl, extracted with EtOAc,washed with brine, dried over anh. Na₂SO₄, filtered and concentrated invacuo. The product was purified by flash chromatography (silica gel,cHex/EtOAc 1:1) to give 180 mg of the title compound as a colorless oil.

[0169] NMR (¹H, CDCl₃): δ 8.45 (bs, 1H), 8.20 (d, 1H), 7.85 (d, 1H),7.85 (2d, 2H), 7.65 (dd, 1H), 7.30 (d, 1H), 7.05 (d, 1H), 6.85 (s, 1H),4.20 (t, 2H), 2.85 (t, 2H), 2.50 (s, 3H). MS (m/z): 514 [MH]⁺.

Intermediate 11 Methanesulfonic acid2-chloro-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-3-ylmethylester

[0170] To a solution of intermediate 3 (308 mg, 1.01 mmol) in anh.CH₂Cl₂ (2.5 mL), at −25° C., under N₂, was added Et₃N (280 μL, 2 eq) andCH₃SO₂Cl (120 μL, 1.5 eq). The reaction mixture was stirred at −25° C.for 2 hr and than at −5° C. for another 2 hr. The reaction mixture wasdiluted with water and extracted with CH₂Cl₂. The combined organicextracts were dried over anh. Na₂SO₄, filtered and concentrated invacuo. The crude product was purified by flash chromatography (silicagel, cHex/EtOAc 6:4→1:1) to give 88 mg of the title compound as acolourless oil.

[0171] NMR (¹H, CDCl₃): δ 7.90 (d, 1H), 7.87 (d, 1H), 7.39 (d, 1H), 7.34(s, 1H), 7.14 (d, 1H), 5.5 (s, 2H), 3.0 (s, 3H), 2.78 (s, 3H). MS (m/z):385 [MH]⁺, Cl

Intermediate 12[2-Chloro-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-3-yl]-acetonitrile

[0172] To a solution of intermediate 11 (88 mg, 0.229 mmol) in anh. DMF(2.5 mL), at 0° C., under N₂, was added KCN (15 mg, 1 eq). The reactionmixture was stirred at room temperature for 5 hr. The reaction mixturewas diluted with water and 1M NaOH and extracted with Et₂O. The combinedorganic extracts were dried over anh. Na₂SO₄, filtered and concentratedin vacuo. The title compound was obtained as a yellow solid (60 mg) andwas used in the next step without further purification.

[0173] NMR (¹H, CDCl₃): δ 7.92 (d, 1H), 7.91 (d, 1H), 7.41 (d, 1H), 7.31(s, 1H), 7.18 (d, 1H), 3.99 (s, 2H), 2.78 (s, 3H). MS (m/z): 316 [MH]⁺,Cl

Intermediate 132-[2-Chloro-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-3-yl]-ethylamine

[0174] To a solution of intermediate 12 (810 mg, 2.571 mmol) in anh. THF(6 mL), at r.t., under N₂, was added BH₃.THF (10.3 mL, 4 eq). Thereaction mixture was stirred at reflux temperature for 2 hr. Thereaction mixture was concentrated in vacuo and diluted with MeOH. 1M HClin Et₂O (7.7 μL, 3 eq) was added at r.t. and the solution was stirred atreflux for 2 hr. The reaction mixture was diluted with water andbasified with 1M NaOH to pH=12. The crude product was purified by flashchromatography (silica gel CH₂Cl₂/MeOH 6:4). The title compound wasobtained as a pale yellow solid (690 mg).

[0175] NMR (¹H, CDCl₃): δ 8.42 (d, 1H), 7.94 (d, 1H), 7.79 (d, 1H), 7.48(s, 1H), 7.07(d, 1H), 2.81 (m, 4H), 2.51 (s, 3H), 2.0 (bs, 2H). MS(m/z): 320 [MH]⁺, Cl

Intermediate 146-Methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

[0176] To a solution of intermediate 13 (640 mg, 2.01 mmol) in dryN-methylpyrrolidinone (13 mL), at r.t., under N₂, was added Et₃N (1.12mL, 4 eq). The reaction mixture was stirred at 110° C. for 7 hr. Thereaction mixture was diluted with water and extracted with EtOAc. Thecombined organic extracts were dried over anh. Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by flashchromatography (silica gel, CH₂Cl₂/MeOH 98:2). The title compound wasobtained as white solid (187 mg).

[0177] NMR (¹H, CDCl₃): δ 7.98 (d, 1H), 7.89 (d, 1H), 7.35 (d, 1H), 7.06(d, 1H), 4.65 (bs, 1H), 3.72 (t, 2H), 3.48 (t, 2H), 2.42 (s, 3H) MS(m/z): 284 [MH]⁺

Intermediate 152-Chloro-3-(3-methoxy-allyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridine

[0178] To a stirred suspension of (methoxy-methyl) triphenylphosphoniumchloride (833 mg, 3 eq.) in anh. THF (4 mL) was added dropwise, at 0°C., under N₂, n-BuLi in hexanes 1.6 M (1.50 ml, 3 eq). The reactionmixture was stirred at r.t. for 15 min before a solution of intermediate6 (258 mg, 1 eq) in anh. THF (3 ml) was added. The reaction mixture wasstirred for 1.5 hr. The mixture was quenched with water and extractedwith EtOAc. The combined organic extracts were dried over anh. Na₂SO₄,filtered and concentrated to dryness in vacuo. The crude product waspurified by flash chromatography (silica gel, cHex/EtOAc 8:2) to give220 mg of the title compound as an unseparable mixture of trans and cis(60/40) vinyl ether (yellow oil, 78%)

[0179] NMR (¹H, CDCl₃): δ 7.88 (d, 1H), 7.79 (d, 1H), 7.36 (d, 1H), 7.19(s, 1H), 7.08 (d, 1H), 6.31 (d, 1H), 4.90 (m, 1H), 3.44 (d, 2H), 3.48(s, 3H), 2.57 (s, 3H). MS (m/z): 347 [MH]⁺, 1 Cl

Intermediate 163-[2-Chloro-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-3-yl]-propionaldehyde

[0180] To a solution of intermediate 15 (370 mg, 1.07 mmol) in THF (5mL) was added HCl 6 N (12 ml, 67.5 eq) and the reaction mixture wasstirred for 13 hr at r.t. A solution of NaHCO₃ was added to the reactionmixture until pH=7 was reached and the aqueous phase was extracted withEtOAc. The combined organic extracts were dried over anh. Na₂SO₄,filtered and concentrated to dryness in vacuo. The crude title compound(335 mg) was used in the following step without further purification.

[0181] NMR (¹H, CDCl₃): δ 9.84 (s, 1H), 7.84 (d, 1H), 7.75 (d, 1H), 7.30(d, 1H), 7.06 (d, 1H), 7.05 (s, 1H), 3.10-3.30 (m, 4 H), 2.55 (s, 3H).MS (m/z): 333 [M+1]⁺, 1Cl

Intermediate 173-[2-Chloro-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-3-yl]-propan-1-ol

[0182] To a solution of intermediate 16 (335 mg, 1 mmol) in anh. CH₃OH(5 mL) were added CeCl₃ (247 mg, 1 eq) and NaBH₄ (38 mg, 1 eq) at r.t.,under N₂. The reaction mixture was stirred for 20 min. The solvent wasremoved in vacuo and the residue was redissolved in EtOAc/H₂O and thelayers were separated. The aqueous layer was extracted with EtOAc, andthe combined organic extracts were dried over anh. Na₂SO₄, filtered, andconcentrated in vacuo. Purification (silica gel, cHex/EtOAc 8:2) of thecrude afforded 277.4 mg of the title compound as a clear oil.

[0183] NMR (¹H, CDCl₃): δ 7.90 (d, 1H), 7.76 (d, 1H), 7.36 (d, 1H), 7.12(s, 1H), 7.07 (d, 1H), 3.70 (m, 2H), 2.90 (t, 2H), 2.58 (s, 3H), 2.20(bt, 1H), 2.04 (m, 2H). MS (m/z): 335 [M+1]⁺, 1Cl

Intermediate 183-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-2-chloro-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridine

[0184] To a solution of intermediate 17 (277.4 mg, 0.83 mmol) in anh.DMF (7 mL) was added imidazole (621 mg, 11 eq), tert-butyldimethylsilylchloride (350 mg, 2.8 eq) and a catalytic amount of DMAP at 0° C. underN₂. The reaction mixture was stirred at room temperature for 2 hr. Thena saturated aqueous solution of NH₄Cl was added to the reaction mixtureand it was extracted with EtOAc. The combined organic extracts weredried over anh. Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified by flash chromatography (silica gel, cHex/EtOAc7:3) to give 347 mg of the title compound as a yellow oil.

[0185] NMR (¹H, CDCl₃): δ 7.89 (d, 1H), 7.81 (d, 1H), 7.34 (d, 1H), 7.20(s, 1H), 7.08 (d, 1H), 3.66 (t, 2H), 2.86 (m, 2H), 2.57 (s, 3H), 1.89(m, 2H), 0.86 (s, 9H), −0.006 (s, 6H). MS (m/z): 449 [M]⁺, 1Cl

Intermediate 19(2,4-Bis-trifluoromethyl-phenyl)-[3-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-2-yl]-amine

[0186] To a vial containing Pd(dba)₃ (17 mg, 0.1 eq),2-(Dicyclobexylphosphino)-2′-methylbiphenyl (20 mg, 0.3 eq) and K₃PO₄(103 mg, 2.7 eq), at r.t., under N₂, were added a solution ofintermediate 18 (80 mg, 0.18 mmol) in anh. DME (0.5 mL) and a solutionof 2,4-bis(trifluoromethyl)aniline (82 mg, 2 eq) in dry DME (0.5 mL).The reaction mixture was submitted to microwave irradiation five times(3×10 min+30 min+60 min) with these observed parameters: P=110 W; T=100°C., p=18 psi. The solution was diluted with water and extracted withEtOAc. The combined organic extracts were dried over anhydrous Na₂SO₄,filtered and concentrated to dryness in vacuo. The crude product waspurified by flash chromatography (silica gel, cHex/Et₂O 7:3) to give 49mg of the title compound as a yellow oil.

[0187] NMR (¹H, CDCl₃): δ 8.58 (d, 1H), 7.89 (d, 1H), 7.85 (d, 1H), 7.77(dd, 1H), 7.76 (d, 1H), 7.34 (d, 1H), 7.23 (bs, 1H), 7.08 (d, 1H), 6.86(s, 1H), 3.67 (t, 2H), 2.69 (m, 2H), 2.3 (s, 3H), 1.90 (m, 2H), 0.8 (s,9H), −0.02 (s, 6H). MS (m/z): 642 [M+1]⁺

Intermediate 203-[2-(2,4-Bis-trifloromethyl-phenylamino)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-3-yl]-propan-1-ol

[0188] To a solution of intermediate 19 (60 mg, 0.094 mmol) in anh. THF(2 mL) was added TEA.3HF (0.046 mL, 3 eq). The reaction mixture wasstirred at room temperature for 12 hr. Then a saturated solution ofNH₄Cl was added to the reaction mixture and it was extracted with EtOAc.The combined organic extracts were dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by flashchromatography (silica gel, cHex/EtOAc 1:1) to give 34.6 mg of the titlecompound as a white solid.

[0189] NMR (¹H, CDCl₃): δ 8.62 (d, 1H), 7.90 (d, 1H), 7.85 (bs, 1H),7.76 (dd, 1H), 7.7 (d, 1H), 7.37 (bs, 1H), 7.36 (d, 1H), 7.07 (d, 1H),6.83 (s, 1H), 3.73 (t, 2H), 2.73 (t, 2H), 2.52 (s, 3H), 2.04 (m, 2H). MS(m/z): 528 [M+1]⁺

Intermediate 212,4-Bis-trifluoromethyl-phenyl)-[3-(3-bromo-propyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl-pyridin-2-yl]-amine

[0190] To a solution of intermediate 20 (34.6 mg, 0.066 mmol) in anh.CH₂Cl₂ (1 mL) was added CBr₄ (44 mg, 2 eq) and PPh₃ (34 mg, 2 eq). Thereaction mixture was stirred at room temperature for 1 hr. Then asaturated aqueous solution of NaHCO₃ was added to the reaction mixtureand it was extracted with EtOAc. The combined organic extracts weredried over Na₂SO₄, filtered and concentrated in vacuo. The crude productwas purified by flash chromatography (silica gel, cHex/EtOAc 7:3) togive 25.7 mg of the title compound as a white solid.

[0191] NMR (¹H, CDCl₃): δ 8.6 (d, 1H), 7.90 (d, 1H), 7.87 (d, 1H), 7.77(m, 1H), 7.37 (d, 1H), 7.15 (bs, 1H), 7.10 (d, 1H), 6.84 (s, 1H), 3.47(t, 2H), 2.78 (m, 2H), 2.52 (s, 3H), 2.3 (m, 2H). MS (m/z): 590 [M]⁺,1Br; 510 [M−Br]⁺

Intermediate 224-[3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-2-ylamino]-3-methyl-benzonitrile

[0192] To a solution of intermediate 8 (186 mg, 0.43 mmol) in anh. DME(1 mL) were added Pd₂(dba)₃ (39 mg, 0.1 eq),2-(dicyclohexylphosphino)-2′-methylbiphenyl (47 mg, 0.3 eq), K₃PO₄ (246mg, 2.6 eq) and 3-methyl4-amino benzonitrile (113 mg, 2 eq) and thereaction mixture was submitted to microwave irradiation (150 W, 100° C.,60 psi) for 20 min. The reaction was then quenched with an aqueoussolution of saturated NH₄Cl, extracted with EtOAc, washed with brine,dried over anh. Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified by flash chromatography (silica gel, cHex/EtOAc8:2) to give 61 mg of the title compound as a white solid.

[0193] NMR (¹H, CDCl₃): δ 8.30 (d, 1H), 8.06 (bs, 1H), 7.89 (d, 1H),7.78 (d, 1H), 7.46 (dd, 1H), 7.44 (d, 1H), 7.36 (d, 1H), 7.09 (d, 1H),6.81 (s, 1H), 4.34 (m, 2H), 2.82 (t, 2H), 2.56 (s, 3H), 2.36 (s, 3H),0.85 (s, 9H), 0.02 (s, 6H). MS (m/z): 531 [MH]⁺.

Intermediate 234-[3-(2-Hydroxy-ethyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-2-ylamino]-3-methyl-benzonitrile

[0194] To a solution of intermediate 22 (61 mg, 0.115 mmol) in anh. THF(2 mL) was added Et₃N.3HF (0.056 ml, 3 eq) and the reaction mixture wasstirred for 15 hr at room temperature. The reaction was then quenchedwith an aqueous solution of saturated NH₄Cl, extracted with EtOAc,washed with brine, dried over anh. Na₂SO₄, filtered and concentrated invacuo. The product was purified by flash chromatography (silica gel,cHex/EtOAc 1:1) to give 46 mg of the title compound as a white solid.

[0195] NMR (¹H, CDCl₃): δ 8.39 (bs, 1H), 8.14 (d, 1H), 7.90 (d, 1H),7.79 (d, 1H), 7.46 (m, 2H), 7.36 (d, 1H), 7.09 (d, 1H), 6.82 (s, 1H),4.34 (m, 2H), 2.83 (t, 2H), 2.54 (s, 3H), 2.34 (s, 3H). MS (m/z): 417[MH]⁺.

Intermediate 244-[3-(2-Hydroxy-ethyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-2-ylamino]-3-trifluoromethyl-benzonitrile

[0196] To a solution of intermediate 8 (106 mg, 0.244 mmol) in anh. DME(1 mL) were added Pd₂(dba)₃ (22 mg, 0.1 eq),2-(dicyclohexylphosphino)-2′-methylbiphenyl (27 mg, 0.3 eq), K₃PO₄ (140mg, 2.7 eq) and 3-trifluoromethyl-4-amino benzonitrile (91 mg, 2 eq) andthe reaction mixture was submitted to microwave irradiation (150 W, 100°C., 60 psi) for 20 min. The reaction was then quenched with an aqueoussolution of saturated NH₄Cl, extracted with EtOAc, washed with brine,dried over anh. Na₂SO₄, filtered and concentrated in vacuo. The productwas purified by flash chromatography (silica gel, cHex/EtOAc 8:2) andthe isolated product containing some unreacted aniline was used in thenext step without further purification.

[0197] To a solution of the mixture obtained above (120 mg) in anh. THF(5 mL) was added Et₃N.3HF (0.063 ml, 3 eq) and the reaction was stirredfor 15 hr at room temperature. The reaction was then quenched with anaqueous solution of saturated NH₄Cl, extracted with EtOAc, washed withbrine, dried over anh. Na₂SO₄, filtered and concentrated in vacuo. Theproduct was purified by flash chromatography (silica gel, cHex/EtOAc1:1). to give 40 mg of the title compound as a white solid.

[0198] NMR (¹H, CDCl₃): δ 8.81 (bs, 1H), 8.22 (d, 1H), 7.90 (d, 1H),7.87 (d, 1H), 7.79 (d, 1H), 7.68 (dd, 1H), 7.37 (d, 1H), 7.17 (d, 1H),6.92 (s, 1H), 4.26 (q, 2H), 2.87 (t, 2H), 2.54 (s, 3H), 2.63 (t, 1H). MS(m/z): 471 [MH]⁺.

Intermediate 25[3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-2-yl]-(2-methyl-trifluoromethoxy-phenyl)-amine

[0199] To a solution of intermediate 8 (110 mg, 0.253 mmol) in anh. DME(1 mL), at r.t., under N₂, were added Pd₂(dba)₃ (23 mg, 0.1 eq),2-(dicyclohexylphosphino)-2′-methylbiphenyl (28 mg, 0.3 eq), K₃PO₄ (145mg, 2.7 eq) and 2-methyl-4-trifluoromethyl aniline (97 mg, 2 eq) and thereaction mixture was submitted to microwave irradiation (150 W, 100° C.,60 psi) for 20 min. The reaction was then quenched with an aqueoussolution of saturated NH₄Cl, extracted with EtOAc, washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo. The product waspurified by flash chromatography (silica gel, cHex/EtOAc 7:3) to give 80mg of the title compound as a yellow oil.

[0200] NMR (¹H, CDCl₃): δ 8.05 (d, 1H), 7.83 (bs, 1H), 7.78 (d, 1H), 7.7(d, 1H), 7.46 (dd, 1H), 7.44 (d, 1H), 7.36 (d, 1H), 7.09 (d, 1H), 6.81(s, 1H), 4.34 (m, 2H), 2.82 (t, 2H), 2.56 (s, 3H), 2.36 (s, 3H), 0.85(s, 9H), 0.023 (s, 6H). MS (m/z): 590 [MH]⁺.

Intermediate 262-[6-Methyl-2-(2-methyl-4-trifluoromethoxy-phenylamino)-4-(3-thiazol-2-yl-pyrazol-1-yl)-pyridin-3-yl]-ethanol

[0201] To a solution of intermediate 25 (80 mg, 0.135 mmol) in anh. THF(2 mL) was added Et₃N.3HF (66 μL, 8 eq) and the reaction mixture wasstirred for 15 hr at room temperature. The reaction was then quenchedwith an aqueous solution of saturated NH₄Cl, extracted with EtOAc,washed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The product was purified by flash chromatography (silica gel,cHex/EtOAc 1:1) to give 48 mg of the title compound as a colorless oil.

[0202] NMR (¹H, CDCl₃): δ 7.91 (bs, 1H), 7.85 (d, 1H), 7.7 (d, 1H), 7.65(d, 1H), 7.30 (d, 1H), 7.15-6.95 (m, 3H), 6.65 (s, 1H), 4.34 (m, 2H),2.83 (t, 2H), 2.54 (s, 3H), 2.34 (s, 3H).

Example 1 Synthesis of Representative Compounds of Structure (IIIa)

[0203]

Example 1-11-(2,4-Bis-trifluoromethyl-phenyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

[0204] To a solution of intermediate 10 (40 mg, 0.078 mmol) in anh.CH₂Cl₂ (2 mL), at r.t., under N₂, were added CBr₄ (52 mg, 2 eq) and PPh₃(41 mg, 2 eq) and the reaction mixture was stirred for 3 hr. Thereaction was then quenched with an aqueous solution of saturated NaHCO₃,extracted with EtOAc, washed with brine, dried over anh. Na₂SO₄,filtered and concentrated in vacuo. The product was purified by flashchromatography (silica gel, cHex/EtOAc 2:1) to give 18 mg of the titlecompound as a white solid.

[0205] Alternatively:

Example 1-11-(2,4-Bis-trifluoromethyl-phenyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

[0206] To a mixture of tris(dibenzylidenacetone)palladium(0) (3.2 mg,0.1 eq), 2-(dicyclohexylphosphino)-2′-methylbiphenyl (3.8 mg, 0.3 eq)and K₃PO₄ (20 mg, 2.8 eq) in a crimp cap microwave vial was added asolution of intermediate 14 (10 mg, 0.035 mmol) and2,4-bis(trifluoromethyl)-bromobenzene (6 μL, 1 eq) in anh. DME (1 mL),under N₂. The reaction mixture was submitted to microwave irradiationfor two cycles (2×10 min) with these observed parameters: P=150 W;T=100° C., p=60 psi Then water (1 mL) was added and the product wasextracted with EtOAc. The combined organic extracts were washed withsat. aq. NaCl (5 mL) and dried over anh. Na₂SO₄. The solids werefiltered and the solvent evaporated to give a crude product, which waspurified by flash chromatography (silica gel, cHex/EtOAc 7:3). The titlecompound was obtained as a colourless oil (1 mg, 0.002 mmol).

Example 1-23-Methyl-4-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl]-benzonitrile

[0207] To a solution of intermediate 23 (44 mg, 0.106 mmol) in anh.CH₂Cl₂ (2 mL) were added CBr₄ (71 mg, 2 eq) and PPh₃ (60 mg, 2 eq) andthe reaction mixture was stirred for 3 hr at room temperature. Thereaction was then quenched with an aqueous solution of saturated NaHCO₃,extracted with EtOAc, washed with brine, dried over anh. Na₂SO₄,filtered and concentrated in vacuo. The product was purified by flashchromatography (silica gel, cHex/EtOAc 4:1) to give 18 mg of the titlecompound as a white solid.

Example 1-34-[6-Methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl]-3-trifluoromethyl-benzonitrile

[0208] To a solution of intermediate 24 (40 mg, 0.085 mmol) in anh.CH₂Cl₂ (2 mL) were added CBr₄ (56 mg, 2 eq) and PPh₃ (45 mg, 2 eq) andthe reaction mixture was stirred for 3 hr at room temperature. Thereaction was then quenched with an aqueous solution of saturated NaHCO₃,extracted with EtOAc, washed with brine, dried over anh. Na₂SO₄,filtered and concentrated in vacuo. The product was purified by flashchromatography (silica gel, cHex/EtOAc 2:1) to give 13 mg of the titlecompound as a white solid.

Example 1-46-Methyl-1-(2-methyl-trifluoromethoxy-phenyl)-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

[0209] To a solution of intermediate 26 (48 mg, 0.101 mmol) in anh.CH₂Cl₂ (2 mL) were added CBr₄ (66 mg, 2 eq) and PPh₃ (53 mg, 2 eq) andthe reaction mixture was stirred for 3 hr at room temperature. Thereaction was then quenched with an aqueous solution of saturated NaHCO₃,extracted with EtOAc, washed with brine, dried over anh. Na₂SO₄,filtered and concentrated in vacuo. The product was purified by flashchromatography (silica gel, cHex/EtOAc 8:2) to give 10 mg of the titlecompound as a white solid.

Example 1-51-(4-Methoxy-2-methyl-phenyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

[0210] To a solution of intermediate 28 (31 mg, 0.075 mmol, 1 eq.) inDCM dry (5 ml), was added CBr₄ (53 mg, 0.16 mmol, 2.1 eq.) andtriphenylphosphine (42 mg, 0.16 mmol, 2.1 eq.) under N₂. The reactionmixture was stirred at RT for 15 hrs. Then water (10 ml) was added andthe aqueous phase was extracted with EtOAc (20 ml). The organic layerwas dried over Na₂SO₄, filtered and concentrated in vacuo. The crude waspurified by flash chromatography (Eluents:cyclohexane/ethyl acetate 7:3)to give 5.2 mg of VSAF/6274/4/1 as a colorless oil.

Example 1-61-(2,4-Bis-trifluoromethyl-phenyl)-6-methyl-4-(3-morpholin-4-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

[0211] Prepared analogously to example 1-1 using4-(1H-pyrazol-3-yl)-morpholine (J. Org. Chem., 1984, 269-276) instead of2-(1H-pyrazol-3-yl)-thiazole in the preparation of intermediate 2.

Example 1-71-(2,4-Bis-trifluoromethyl-phenyl)-6-methyl-4-(3-pyridin-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

[0212] Prepared analogously to example 1-1 using2-(1H-Pyrazol-3-yl)-pyridine (commercially available) instead of2-(1H-pyrazol-3-yl)-thiazole in the preparation of intermediate 2.

Example 1-84-[1,3′]Bipyrazolyl-1′-yl-1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

[0213] Prepared analogously to example 1-1 using 1′H-[1,3′]bipyrazolyl(from 1H-pyrazol-3-ylamine: J. Heterocycl. Chem., 1983, 1629-1639; thenJ. Heteroycl. Chem., 1989, 733-738) instead of2-(1H-pyrazol-3-yl)-thiazole in the preparation of intermediate 2.

[0214] All the analytical data are set forth in the following Table 1-1.TABLE 1-1 (IIIa)

Cpd. No. R R₁ R₂—R₃— Analytical Data 1-1 2,4-bistrifluoro- methylphenylCH₃

NMR (¹H, DMSO): δ 8.64 (d, 1H), 8.17 (dd, 1H), 8.13 (d, 1H), 7.94 (d,1H), 7.84 (d, 1H), 7.80 (d, 1H), 7.09 (m, 2H), 3.97 (t, 2H), 3.56 (t,2H), 2.24 (s, 3H). MS (m/z): 496 [MH]⁺. 1-2 2-methyl-4-cyano CH₃

NMR (¹H, DMSO): δ 8.02 (d, 1H), 7.90 (d, 1H), 7.59 (d, 1H), 7.53 (dd,1H), 7.41 (d, 1H), 7.38 (d, 1H), 6.76 (s, 1H), 4.04 (t, 2H), 3.62 (t,2H), 2.41 (s, 3H), 2.33 (s, 3H). MS (m/z): 399 [MH]⁺. 1-32-trifluoromethyl- 4-cyano CH₃

NMR (¹H, CDCl₃): δ 8.00 (m, 2H), 7.9-7.8 (d + d, 2H), 7.65 (d, 1H), 7.35(d, 1H), 7.10 (d, 1H), 6.80 (s, 1H), 4.00 (t, 2H), 3.60 (t, 2H), 3.56(t, 2H), 2.40 (s, 3H). MS (m/z): 453 [MH]⁺. 1-4 2-methyl-4-tri-fluoromethoxy CH₃

NMR (¹H, DMSO): δ 8.01 (d, 1H), 7.89 (d, 1H), 7.5 (d, 1H), 7.45 (dd,1H), 7.20 (d, 1H), 7.1 (dd, 2H), 6.65 (s, 1H), 3.9 (t, 2H), 3.56 (t,2H), 2.32 (s, 3H), 2.25 (s, 3H). MS (m/z): 458.5 [MH]⁺. 1-52-methyl-4-methoxy CH₃

NMR (¹H, CDCl₃): δ 7.97 (d, 1H), 7.86 (d, 1H), 7.33 (d, 1H), 7.17 (d,1H), 7.10 (d, 1H), 6.78 (m, 2H), 6.61 (s, 1H), 3.90 (t, 2H), 3.80 (s,3H), 3.52 (t, 2H), 2.34 (s, 3H), 2.23 (s, 3H). MS (m/z): 404 [M + 1]⁺

Example 2 Synthesis of Representative Compounds of Structure (IIIb)

[0215]

[0216] All the analytical data are set forth in the following Table 2-1.

Example 2-11-(2,4-Bis-trifluoromethyl-phenyl)-7-methyl-5-(3-thiazol-2-yl-pyrazol-1-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine

[0217] To a solution of intermediate 21 (24.8 mg, 0.042 mmol) in anh.N-metylpyrrolidinone (2 mL) was added Et₃N (12 μL, 2 eq) under N₂. Thereaction mixture was submitted to microwave irradiation for 10 min withthese observed parameters: P=90 W; T=99° C., p=6 psi. Then a saturatedaqueous solution of NH₄Cl was added to the reaction mixture and theaqueous phase was extracted with EtOAc. The combined organic extractswere washed with a saturated solution of NH₄Cl (3×), dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product was purified bySCX Column (Eluents: CH₂Cl₂, MeOH and a solution of conc. NH₄OH in MeOH(25%) to elute the desired product) to give 18.4 mg of the titlecompound as a white foam. TABLE 2-1 Cpd. No. R R₁ R₂—R₃— Analytical Data2-1 2,4-bistrifluoro- methylphenyl CH₃

NMR (¹H, CDCl₃): δ 8.02 (bs, 1H), 7.89 (d, 1H), 7.88 (dd, 1H), 7.74 (d,1H), 7.46 (d, 1H), 7.35 (d, 1H), 7.06 (d, 1H), 6.59 (s, 1H), 3.66 (bm,2H), 2.97 (bm, 1H), 2.85 (bm, 1H), 2.18 (s, 3H), 2.09 (bm, 1H), 2.04(bm, 1H). MS (m/z): 510 [M + 1]⁺

Example 3 CRF Binding Activity

[0218] CRF binding affinity has been determined in vitro by thecompounds' ability to displace ²⁵¹I-oCRF and ¹²⁵I-Sauvagine for CRF1 andCRF2 SPA, respectively, from recombinant human CRF receptors expressedin Chinese Hamster Ovary (CHO) cell membranes. For membrane preparation,CHO cells from confluent T-flasks were collected in SPA buffer(HEPES/KOH 50 mM, EDTA 2 mM; MgCl₂ 10 mM, pH 7.4.) in 50 mL centrifugetubes, homogenized with a Polytron and centrifuged (50′000 g for 5 minat 4° C.: Beckman centrifuge with JA20 rotor). The pellet wasresuspended, homogenized and centrifuged as before. The SPA experimenthas been carried out in Optiplate by the addition of 100 μL the reagentmixture to 1 μL of compound dilution (100% DMSO solution) per well. Theassay mixture was prepared by mixing SPA buffer, WGA SPA beads (2.5mg/mL), BSA (1 mg/mL) and membranes (50 and 5 μg of protein/mL for CRF1and CRF2 respectively) and 50 pM of radioligand.

[0219] The plate was incubated overnight (>18 hrs) at room temperatureand read with the Packard Topcount with a WGA-SPA ¹²⁵I countingprotocol.

Example 4 CRF Functional Assay

[0220] Compounds of the invention were characterised in a functionalassay for the determination of their inhibitory effect. Human CRF—CHOcells were stimulated with CRF and the receptor activation was evaluatedby measuring the accumulation of cAMP.

[0221] CHO cells from a confluent T-flask were resuspended with culturemedium without G418 and dispensed in a 96-well plate, 25′000 c/well, 100μL/well and incubated overnight. After the incubation the medium wasreplaced with 100 μL of cAMP IBMX buffer warmed at 37° C. (5 mM KCl, 5mM NaHCO₃, 154mM NaCl, 5 mM HEPES, 2.3 mM CaCl₂, 1 mM MgCl₂; 1 g/Lglucose, pH 7.4 additioned by 1 mg/mL BSA and 1 mM IBMX) and 1 μL ofantagonist dilution in neat DMSO. After 10 additional minutes ofincubation at 37° C. in a plate incubator without CO2, 1 μL of agonistdilution in neat DMSO was added. As before, the plate was incubated for10 minutes and then cAMP cellular content was measured by using theAmersham RPA 538 kit.

[0222] All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

[0223] It is to be understood that the present invention covers allcombinations of particular and preferred groups described herein above.

[0224] The application of which this description and claims forms partmay be used as a basis for priority in respect of any subsequentapplication. The claims of such subsequent application may be directedto any feature or combination of features described herein. They maytake the form of product, composition, process, or use claims and mayinclude, by way of example and without limitation, the following claims:

1. Compounds of formula (I) including stereoisomers, prodrugs andpharmaceutically acceptable salts or solvates thereof

R is aryl or heteroaryl, each of which may be substituted by 1 to 4groups selected from: halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, —C(O)R₅, nitro,—NR₆R₇, cyano, and a group R₈; R₁ is hydrogen, C1-C6 alkyl, C2-C6alkenyl, C2-C6 alkynyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, halogen,NR₆R₇ or cyano; R₂ is hydrogen, C3-C7 cycloalkyl, or a group R₉; R₃ isC3-C7 cycloalkyl, or a group R₉; or R₂ and R₃ together with N form a5-14 membered heterocycle, which may be substituted by 1 to 3 R₁₀groups; R₄ is hydrogen, C1-C6 alkyl, halogen or halo C1-C6 alkyl; R₅ isa C1-C4 alkyl, —OR₆ or —NR₆R₇; R₆ is hydrogen or C1-C6 alkyl; R₇ ishydrogen or C1-C6 alkyl; R₈ is a 5-6 membered heterocycle, which may besaturated or may contain one to three double bonds, and which may besubstituted by 1 or more R₁₁ groups; R₉ is a C1-C6 alkyl that may besubstituted by one or more groups selected from: C3-C7 cycloalkyl, C1-C6alkoxy, haloC1-C6 alkoxy, hydroxy, haloC1-C6 alkyl; R₁₀ is a group R₈,C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, hydroxy, halogen, nitro,cyano, C(O)NR₆R₇, phenyl which may be substituted by 1 to 4 R₁₁ groups;R₁₁ is C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl,C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, hydroxy, halogen,nitro, cyano, or C(O)NR₆R₇; X is carbon or nitrogen; n is 1 or
 2. 2.Compounds, according to claim 1, in which R₂ and R₃ together with N forma 5-14 membered heterocyclic group, which may be substituted by 1 to 3R₁₀ groups.
 3. Compounds, according to claim 1, of general formula (Ia)

in which R, R₁, R₂, R₃ R₄ and X are defined as in claim
 1. 4. Compounds,according to claim 3, of general formula (IIa)

in which R, R₁, R₂, R₄ and R₃ are defined as in claim
 1. 5. Compounds,according to claim 4, in which the group NR₂R₃ represents a 5-6 memberedheterocyclic group, which may be substituted by 1 to 3 R₈ groups. 6.Compounds, according to claim 5, of general formula (IIIa)

in which R, R₁, R₄ and R₈ are defined as in claim
 1. 7. Compounds,according to claim 1, of general formula (Ib)

in which R, R₁, R₂, R₃ R₄ and X are defined as in claim
 1. 8. Compounds,according to claim 7, of general formula (IIIb)

in which R, R₁, R₂, R₄ and R₃ are defined as in claim
 1. 9. Compounds,according to any of claims from 1 to 8, wherein R₁ is C1-C3 alkyl groupor halo C1-C3 alkyl group and R₄ is hydrogen.
 10. Compounds, accordingto any of claims from 1 to 9, wherein R is an aryl group selected from:2,4-dichlorophenyl, 2-chloro4-methylphenyl, 2-chloro-4-trifluoromethyl,2-chloro-4-methoxyphenyl, 2,4,5-trimethylphenyl, 2,4-dimethylphenyl,2-methyl-4-methoxyphenyl, 2-methyl-4-chlorophenyl,2-methyl-4-trifluoromethyl, 2,4-dimethoxyphenyl,2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4-chlorophenyl,3-methoxy-4-chlorophenyl, 2,5-dimethoxy-4-chlorophenyl,2-methoxy-4-isopropylphenyl, 2-methoxy-4-trifluoromethylphenyl,2-methoxy-4-isopropylphenyl, 2-methoxy-4-methylphenyl,2-trifluoromethyl-4-chlorophenyl, 2,4-trifluoromethylphenyl,2-trifluoromethyl-4-methylphenyl, 2-trifluoromethyl-4-methoxyphenyl,2-bromo-4-isopropylphenyl, 2-methyl-4-cyanophenyl,2-chloro-4-cyanophenyl, 4-methyl-6-dimethylaminopyridin-3-yl,3,5-dichloro-pyridin-2-yl, 2,6-bismethoxy-pyridin-3-yl and3-chloro-5-trichloromethyl-pyridin-2-yl.
 11. A compound, according toany of claims from 1 to 10, selected in a group consisting from:1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine;1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine;3-methyl4-[6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl]-benzonitrile;4-[6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl]-3-trifluoromethyl-benzonitrile;6-methyl-1-(2-methyl-4-trifluoromethoxy-phenyl)-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine;1-(2,4-bis-trifluoromethyl-phenyl)-7-methyl-5-(3-thiazol-2-yl-pyrazol-1-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine;1-(4-methoxy-2-methyl-phenyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-4-(3-morpholin-4-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-4-(3-pyridin-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine4-[1,3′]bipyrazolyl-1′-yl-1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine.12. A process for the preparation of a compound of formula (I) asclaimed in claim 1, which comprises
 13. The use of a compound accordingto any of claims from 1 to 11, in the preparation of a medicament foruse in the treatment of conditions mediated by CRF(corticotropin-releasing factor).
 14. The use of a compound according toclaim 13, in the preparation of a medicament for use in the treatment ofdepression and anxiety.
 15. The use of a compound according to claim 14,in the preparation of a medicament for use in the treatment of IBS(irritable bowel disease) and IBD (inflammatory bowel disease).
 16. Acompound according to any of claims 1 to 11, for use in the treatment ofconditions mediated by CRF (corticotropin-releasing factor).
 17. Acompound according to claim 16, for use in the treatment of depressionand anxiety.
 18. A compound according to claim 17, for use in thetreatment of IBS (irritable bowel disease) and IBD (inflammatory boweldisease).
 19. A pharmaceutical composition comprising a compoundaccording to any of claims from 1 to 11, in admixture with one or morephysiologically acceptable carriers or excipients.
 20. A method for thetreatment of a mammal, including man, in particular in the treatment ofconditions mediated by CRF (corticotropin-releasing factor), comprisingadministration of an effective amount of a compound according to any ofclaims from 1 to
 11. 21. A method, according to claim 20, in thetreatment of depression and anxiety, comprising administration of aneffective amount of a compound according to any of claims 1 to
 11. 22. Amethod, according to claim 21, in the treatment of IBS (irritable boweldisease) and IBD (inflammatory bowel disease), comprising administrationof an effective amount of a compound according to any of claims 1 to 11.